NM_000135.3:c.2003G>T (p.Ser668Ile) is a missense variant in FANCA, a gene associated with autosomal recessive Fanconi anemia. The variant is extremely rare in population databases with an allele frequency of 6.42×10⁻⁶ in gnomAD v2.1 and 3.22×10⁻⁶ in gnomAD v4.1, meeting PM2 (moderate).1 Multiple in silico tools predict a benign effect: REVEL score 0.276, BayesDel score -0.261, and SpliceAI max delta 0.00, meeting BP4 (supporting benign).2 The variant is classified as Uncertain significance in ClinVar (VCID 2161267) by four clinical laboratories with criteria provided but no expert panel review. No pathogenic assertion from a reputable source exists.3 No functional studies, case-control data, segregation data, de novo observations, or variant-specific literature citations were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no curated PMIDs.4 The only applicable evidence criteria are PM2 (moderate, supporting pathogenicity) and BP4 (supporting benign). These offset each other, leaving the variant with no net evidence weight toward either pathogenic or benign classification. The variant remains a Variant of Uncertain Significance.5
FANCA
Final classification
VUS
FANCA c.2003G>T · p.Ser668Ile
FANCA
NM_000135.3:c.2003G>T (p.Ser668Ile) is a missense variant in FANCA, a gene associated with autosomal recessive Fanconi anemia. The variant is extremely rare in population databases with an allele frequency of 6.42×10⁻⁶ in gnomAD v2.1 and 3.22×10⁻⁶ in gnomAD v4.1, meeting PM2 (moderate).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FANCA c.2003G>T
PM2 + BP4
→
VUS
Gene diagram
· NM_000135.3 · variants mapped to exon structure
FANCA
NM_000135.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
NM_000135.3:c.2003G>T is extremely rare in population databases. In gnomAD v2.1 exomes, the variant is observed at an allele frequency of 6.42×10⁻⁶ (1/155,698 alleles; MAF 0.00064%), far below the 0.1% threshold for PM2. In gnomAD v4.1, the AF is 3.22×10⁻⁶ (5/1,550,610 alleles; MAF 0.00032%). No homozygotes are reported in either dataset. The variant is absent from gnomAD-Canada. This ultra-rare population frequency supports a moderate evidence weight for pathogenicity under the ACMG/AMP framework.
gnomAD v2.1: AF=6.42e-06 (1/155698 alleles)0 homozygotes
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest NM_000135.3:c.2003G>T (p.Ser668Ile) has no deleterious impact. REVEL predicts a benign score of 0.276 (well below the 0.5 threshold commonly used for pathogenic prediction). BayesDel predicts a benign score of -0.261 (negative scores indicate benign). SpliceAI predicts no splicing alteration (max delta score = 0.00). The concordance of multiple in silico predictors supports a supporting benign evidence weight.
REVEL score: 0.276 (benignbelow 0.5)BayesDel score: -0.261 (benign
Assessed · not applied
Pathogenic
PS1
No evidence of a previously established pathogenic missense variant at the same amino acid position (Ser668) producing the same amino acid change (Ser668Ile) was identified in ClinVar, the literature, or any other source reviewed.
PS2
No de novo data are available for NM_000135.3:c.2003G>T in any source reviewed.
PS3
No functional experimental data were identified for NM_000135.3:c.2003G>T (p.Ser668Ile).
PS4
No case-control studies or case series demonstrating enrichment of NM_000135.3:c.2003G>T in affected individuals over controls were identified.
PM1
The variant does not lie in a statistically significant mutational hotspot as assessed by cancerhotspots.org (residue_significant=false).
PM5
No pathogenic missense variant at the same amino acid residue (Ser668) with a different amino acid change was identified as a comparator.
PM6
No de novo occurrence of NM_000135.3:c.2003G>T has been reported with confirmed maternity and paternity.
PP1
No segregation data are available for NM_000135.3:c.2003G>T.
PP2
PP2 requires a low rate of benign missense variation in the gene and demonstration that missense variants are a common disease mechanism.
PP3
Multiple lines of in silico computational evidence do not support a deleterious effect of this variant.
PP4
No patient phenotype or clinical data specific to NM_000135.3:c.2003G>T are available.
PP5
No reputable source has classified NM_000135.3:c.2003G>T as pathogenic.
Benign
BA1
The gnomAD allele frequency of NM_000135.3:c.2003G>T is 6.42×10⁻⁶ (v2.1) and 3.22×10⁻⁶ (v4.1), far below the 1% BA1 threshold.
BS1
The gnomAD allele frequency (6.42×10⁻⁶) is far below the 0.3% BS1 threshold.
BS2
No data are available regarding observation of NM_000135.3:c.2003G>T in healthy adult individuals.
BS3
No functional experimental data exist demonstrating that NM_000135.3:c.2003G>T (p.Ser668Ile) has no deleterious effect on protein function or splicing.
BS4
No segregation data are available to assess lack of segregation with disease.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2
No data are available regarding observation of NM_000135.3:c.2003G>T in trans with a known pathogenic variant in FANCA (relevant for recessive Fanconi anemia) or in cis with a pathogenic variant.
BP5
No case has been identified where NM_000135.3:c.2003G>T is observed in an individual with an alternate molecular basis for disease.
BP6
No reputable source has classified NM_000135.3:c.2003G>T as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.22454e-06; MAF= 0.00032%, 5/1550610 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.88687e-05; MAF= 0.00489%, 2/40926 alleles, homozygotes = 0); grpmax FAF= 8.1e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.42269e-06; MAF= 0.00064%, 1/155698 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.8433e-05; MAF= 0.00884%, 1/11308 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00032%
· 5 / 1,550,610
0 hom · FAF 0.00081%
0 hom · FAF 0.00081%
East Asian 2 / 40,926 |
0.0049% |
Remaining individuals 1 / 60,076 |
0.0017% |
South Asian 1 / 84,044 |
0.0012% |
European (non-Finnish) 1 / 1,146,544 |
8.7e-05% |
+ 6 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00064%
· 1 / 155,698
0 hom
0 hom
East Asian 1 / 11,308 |
0.0088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 2161267)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.276. BayesDel score = -0.261458.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCA, a DNA repair protein, is infrequently altered in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
24022298 ↗
Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].
CLINVAR